Development of the Respiratory System and Body Cavities

Summary

As covered in Chapter 4 , shortly after the three germ layers form during gastrulation, body folding forms the endodermal foregut at the cranial end of the embryo, thereby delineating the inner tube of the tube-within-a-tube body plan . On day 22, the foregut produces a ventral evagination called the respiratory diverticulum or lung bud , which is the primordium of the lungs. As the lung bud grows, it remains ensheathed in a covering of splanchnopleuric mesoderm, which will give rise to the lung connective tissue and vasculature and to the connective tissue, cartilage, and muscle within the bronchi. On days 26 to 28, the lengthening lung bud bifurcates into left and right primary bronchial buds , which will give rise to the two lungs. In the fifth week, a second generation of branching produces three secondary bronchial buds on the right side and two on the left. These are the primordia of the future lung lobes. The bronchial buds and their splanchnopleuric sheath continue to grow and bifurcate, gradually filling the pleural cavities. By week 16, the 16th round of branching generates terminal bronchioles , which subsequently divide into two or more respiratory bronchioles . By week 26, these respiratory bronchioles have become invested with capillaries and are called terminal sacs or primitive alveoli . Between 36 weeks and birth, the alveoli mature. Additional alveoli continue to be produced into early adulthood.

During the fourth week, partitions form to subdivide the intraembryonic coelom into pericardial, pleural, and peritoneal cavities. The first partition to develop is the septum transversum , a block-like wedge of mesoderm that forms a ventral structure partially dividing the coelom into a thoracic primitive pericardial cavity and an abdominal peritoneal cavity . Cranial body folding and differential growth of the developing head and neck regions translocate this block of mesoderm from the cranial edge of the embryonic disc caudally to the position of the future diaphragm. Coronal pleuropericardial folds meanwhile form on the lateral body wall of the primitive pericardial cavity and grow medially to fuse with each other and with the ventral surface of the foregut mesoderm, thus subdividing the primitive pericardial cavity into a definitive pericardial cavity and two pleural cavities . The pleural cavities initially communicate with the peritoneal cavity through a pair of pericardioperitoneal canals passing dorsal to the septum transversum. However, a pair of transverse pleuroperitoneal folds grow ventrally from the dorsal body wall over the transverse septum and fuse, thus closing off the pericardioperitoneal canals. The fused pleuroperitoneal folds form the major portion of the future diaphragm.

As covered in Chapter 6 , as a result of folding, the amnion, which initially arises from the dorsal margin of the embryonic disc ectoderm, is carried ventrally to enclose the entire embryo, taking origin from the umbilical ring surrounding the roots of the vitelline duct and connecting stalk. The amnion also expands until it fills the chorionic space and fuses with the chorion. As the amnion expands, it encloses the connecting stalk and yolk sac neck in a sheath of amniotic membrane. This composite structure becomes the umbilical cord .

Development of Lungs and Respiratory Tree

Animation 11.1: Development of Lungs.

Animations are available online at StudentConsult.

Development of the esophagus, stomach, trachea, and lungs from the foregut region is tightly linked ( Fig. 11.1A ). Hence defects in the development of the foregut region often involve both the cranial level of the gastrointestinal system and the respiratory system (see Chapter 14, Chapter 17 for further coverage of the development of the foregut region). Development of the lungs begins as early as day 22 with formation of a ventral outpouching of the endodermal foregut called the respiratory diverticulum (see Fig. 11.1B ). This bud grows ventrocaudally through the mesenchyme surrounding the foregut, and on days 26 to 28, it undergoes a first bifurcation, splitting into right and left primary bronchial (or lung ) buds . These buds are the rudiments of the two lungs and the right and left primary bronchi , and the proximal end (stem) of the diverticulum forms the trachea and larynx . The latter opens into the pharynx via the glottis , a passageway formed at the original point of evagination of the diverticulum. As the primary bronchial buds form, the stem of the diverticulum begins to separate from the overlying portion of the pharynx, which becomes the esophagus . During weeks 5 and 16, the primary bronchial buds undergo about 16 rounds of branching to generate the respiratory tree of the lungs. The pattern of branching of the lung endoderm is regulated by the surrounding mesenchyme, which invests the buds from the time that they first form. The stages of development of the lungs are summarized in Table 11.1 .

The first round of branching of the primary bronchial buds occurs early in the fifth week (see Fig. 11.1B ). This round of branching is highly stereotypical and yields three secondary bronchial buds on the right side and two on the left. The secondary bronchial buds give rise to the lung lobes : three in the right lung and two in the left lung. During the fifth week, a more variable round of branching typically yields 10 tertiary bronchial buds on both sides; these become the bronchopulmonary segments of the mature lung.

By week 16, after about 14 more branchings, the respiratory tree produces small branches called terminal bronchioles ( Fig. 11.2 ). Between 16 and 26 weeks, each terminal bronchiole divides into two or more respiratory bronchioles , and the mesodermal tissue surrounding these structures becomes highly vascularized. Beginning in week 24, the first respiratory bronchioles begin to sprout a final generation of stubby branches. These branches develop in craniocaudal progression, forming first at more cranial terminal bronchioles. The first-formed wave of terminal branches are invested in a dense network of capillaries and are called terminal sacs (primitive alveoli) . Limited gas exchange is possible at this point, but the alveoli are still so few and immature that infants born at this age may die of respiratory insufficiency without adequate therapy (covered in a following “In the Clinic” entitled “Lung Maturation and Survival of Premature Infants”).

Additional terminal sacs continue to form and differentiate in craniocaudal progression both before and after birth. The process is largely completed by 2 years of age. About 20 to 70 million terminal sacs are formed in each lung before birth; the total number of alveoli in the mature lung is 300 to 400 million. Continued thinning of the squamous epithelial lining of the terminal sacs begins just before birth, resulting in the differentiation of these primitive alveoli into mature alveoli.

The development of the lung during fetal and postnatal life is often subdivided into four phases. The pseudoglandular phase begins at around 5 weeks and continues through 16 weeks of gestation. It is characterized by the presence of terminal bronchi consisting of thick-walled tubes surrounded by dense mesenchyme. It is during this phase when fetal breathing movements are beginning to move fluids in and out of the tubes. The canalicular phase begins around the fourth month of gestation ( Fig. 11.3A ). It is characterized by thinning of the walls of the tubes as the lumens of the bronchi enlarge. During the canalicular phase, the lung becomes highly vascularized. The saccular phase begins around the beginning of the sixth to seventh month of gestation (see Fig. 11.3B ). It is characterized by further thinning of the tubes to form numerous sacculi lined with type I and II alveolar cells (the former form the surface for gas exchange, and the latter respond to damage to type I cells by dividing and replacing them; as covered in the “In the Clinic” entitled “Lung Maturation and Survival of Premature Infants,” type II cells are the source of pulmonary surfactant). The alveolar phase begins shortly before birth, typically around the beginning of the 36th week of gestation, and continues into postnatal life (see Fig. 11.3C ). It is characterized by the formation of mature alveoli.

An important process of septation , which further subdivides the alveoli, occurs after birth and up to early adulthood. Each septum formed during this process contains smooth muscle and capillaries.

The lung is a composite of endodermal and mesodermal tissues. The endoderm of the respiratory diverticulum gives rise to the mucosal lining of the bronchi and to the epithelial cells of the alveoli. The remaining components of the lung, including muscle and cartilage supporting the bronchi and the visceral pleura covering the lung, are derived from the splanchnopleuric mesoderm, which covers the bronchi as they grow out from the mediastinum into the pleural space. The lung vasculature is thought to develop via angiogenesis (i.e., sprouting from neighboring vessels; angiogenesis is covered in Chapter 13 ).

In the Clinic

Esophageal Atresia and Tracheoesophageal Fistula

Esophageal atresia (EA; a blind esophagus) and tracheoesophageal fistula (TEF; an abnormal connection between tracheal and esophageal lumens resulting from failure of the foregut to separate completely into trachea and esophagus; also called esophagotracheal fistula ) are usually found together and occur in 1 of 3000 to 5000 births ( Fig. 11.4 ). However, many variations in these defects are known, including an EA that connects to the trachea, forming a proximal TEF (with or without a distal TEF; the latter is illustrated in Fig. 11.4 ), an isolated TEF (i.e., without an EA), and an isolated EA (i.e., without a TEF). In addition, both of these defects can be associated with other defects (e.g., EA with cardiovascular defects, such as tetralogy of Fallot—covered in Chapter 12 ; TEF with VATER or VACTERL association —covered in Chapter 3 ). Both EA and TEF are dangerous to the newborn because they allow milk or other fluids to be aspirated into the lungs. Hence they are surgically corrected in the newborn. In addition to threatening survival after birth, EA has an adverse effect on the intrauterine environment before birth: the blind-ending esophagus prevents the fetus from swallowing amniotic fluid and returning it to the mother via the placental circulation. This leads to an excess of amniotic fluid ( polyhydramnios ) and consequent distention of the uterus.